Inflammatory mediators, including cytokines and chemokines, are associ
ated with the pathology of chronic liver disease. Interleukin-8 (IL-8)
in humans and macrophage inflammatory protein-2 (MIP-2) in rodents, b
oth members of the C-X-C family of chemokines, are particularly potent
neutrophil attractants and have been implicated in chronic liver dise
ases. In the liver, cytokine secretion is usually associated with nonp
arenchymal cells, particularly Kupffer cells. In the present studies,
chemokine gene expression and secretion were investigated in hepatocyt
es treated with various stimulators. Using human Hep G2 cells, it was
demonstrated that, in contrast to lipopolysaccharides (LPS), both tumo
r necrosis factor-alpha (TNF-alpha) and H2O2 are potent inducers of IL
-8, presumably acting via protein kinase C (PKC)-dependent pathways. M
IP-2 expression occurred in freshly isolated rat hepatocytes following
treatment with TNF-alpha, LPS, and to a lesser degree, H2O2, Both IL-
8 and MIP-2 secretion were inhibited, although to varying degrees, by
such antioxidants as TMTU, DMSO, catalase, and N-acetylcysteine. Furth
ermore, in vitro TNF-alpha neutralization experiments and transfection
of Hep G2 cells with an IL-8 construct confirmed that TNF-alpha and H
2O2 directly stimulate IL-8 secretion. RT-PCR analyses indicated that
chemokine secretion induced by these agents operates via increased gen
e expression. Furthermore, a variety of cytokine genes were found to b
e expressed by hepatocytes, including MCP-1, cytokine-induced neutroph
il chemoattractant (CINC), and IL-6, Taken together, these studies ind
icate that hepatocytes respond to biologically relevant levels of comm
on activators, including H2O2, to produce cytokines and chemokines tha
t contribute to pathophysiologic and repair processes in the liver.